Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression.
Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression.
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DOI：
10.1016/j.neo.2016.09.001
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发表时间：
2016-11
期刊：
影响因子：
4.8
通讯作者：
Khanna, Chand
中科院分区：
文献类型：
--
作者：
Lizardo, Michael M.;Morrow, James J.;Miller, Tyler E.;Hong, Ellen S.;Ren, Ling;Mendoza, Arnulfo;Halsey, Charles H.;Scacheri, Peter C.;Helman, Lee J.;Khanna, Chand
转移是所有癌症死亡的90%以上的原因。尽管如此，目前临床上使用的大多数抗癌治疗药物在治疗已确定的转移瘤方面的疗效有限。在这里，我们确定内质网伴侣蛋白，葡萄糖调节蛋白78(GRP78)，在几个高转移癌细胞模型中是转移依赖性的。我们发现，当高转移癌细胞在肺微环境中定植时，GRP78持续上调，通过短发夹状RNA或小分子IT-139治疗GRP78上调的缓解，目前正在进行临床研究，用于治疗原发肿瘤，抑制肺微环境中的转移生长。在四种高转移细胞系模型中，GRP78的上调受到抑制，转移潜能也随之降低：三种人骨肉瘤和一种小鼠乳腺癌。最后，我们发现，在实验转移的活体动物模型中，高转移癌细胞中GRP78的下调显著延长了中位生存期。总体而言，我们的数据表明GRP78是抗转移治疗开发的一个有吸引力的靶点。
Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies.
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在癌症转移中重新审视种子和土壤。
DOI：
10.1016/j.biocel.2009.01.015
发表时间：
2009-07
期刊：
The international journal of biochemistry & cell biology
影响因子：
--
作者：
Mendoza M;Khanna C
通讯作者：
Khanna C
影响因子：
6.4
作者：
Hedley, Benjamin D.;Welch, Danny R.;Chambers, Ann F.
通讯作者：
Chambers, Ann F.
影响因子：
11.2
作者：
Ren L;Hong SH;Chen QR;Briggs J;Cassavaugh J;Srinivasan S;Lizardo MM;Mendoza A;Xia AY;Avadhani N;Khan J;Khanna C
通讯作者：
Khanna C
影响因子：
5.6
作者：
Roller C;Maddalo D
通讯作者：
Maddalo D
影响因子：
15.9
作者：
Mendoza, Arnulfo;Hong, Sung-Hyeok;Khanna, Chand
通讯作者：
Khanna, Chand